Population Genomics of Host-Microbiome Interactions The composition of the microbial communities that colonize the human body varies widely across individuals and populations, and has been associated with numerous host traits and diseases. Although the microbiome is influenced by environmental factors, a strong host genetic factor is also expected to control the interaction between humans and the microbiome. Understanding the relative role of genetic and environmental factors in host-microbiome interactions is a central goal in human disease research. However, we know very little about the genomic factors that control the interaction between humans and the microbiome and their effect on complex human disease. It is often difficult to disentangle genetic from environmental effects on the microbiome, and studies only consider the microbiome in a single time point, which could be problematic given the microbiome can vary dramatically day-to-day and throughout an individual's life. Moreover, as most microbiome studies identify correlations, we do not know how inter-individual and inter-population variation in microbiome composition affects host physiology. In this proposal, I outline a long-term research strategy to address these critical gaps in knowledge. Research in my lab is based on the hypothesis that the microbiome can be considered a quantitative trait, and thus we can directly map host genomic factors controlling the variation in the microbiome, as well as identify individual host genes and pathways that are regulated by the microbiome. Here, I outline my lab's research program for the next five years, designed to answer fundamental questions about the genetic basis of host- microbiome interactions via three broad, complementary Project Areas, aiming to: (1) collect and integrate host and microbiome genomic data to achieve a systems-level understanding of host-microbiome molecular interactions in the colon; (2) characterize the heritability of life-long longitudinal microbiome dynamics in a primate model system; and (3) use novel in vitro and ex vivo systems to understand the effect of inter- population variation in the microbiome on host gene regulation and describe the underlying regulatory mechanism. The proposed research program will provide a systems-level view of the molecular interactions between host genes and microbial taxa, genes, and pathways in the gut; a characterization of how microbiome dynamics and taxa are controlled by host genetic variation; and a description of the mechanism with which the microbes regulate host genes. These results would transform our understanding of the interplay between human genomics and the microbiome, explain how this interaction affects disease, and would enable development of microbiome-based therapeutics and diagnostics that improve human health.